Nearly half of all intensive care unit (ICU) admissions consist of adults =65 years old, an age group that is at high risk for developing cognitive decline and delirium in the ICU. Over 50% and 70% of critically ill cardiac surgery patients develop post-operative delirium (POD) and post-operative cognitive decline (POCD), respectively. These two forms of acute cognitive dysfunction are associated with increased mortality and poor functional recovery. While distinct conditions, POD has been associated with the subsequent development of POCD, suggesting a mechanistic link. No proven pharmacologic treatments targeting the prevention of both POD and POCD in elderly patients exist to date. Recent data suggest that insulin administered into the central nervous system via intranasal delivery improves cognitive function in elderly patients with Alzheimer's disease and mild cognitive impairment. However, its utility in preventing POD and POCD in elderly critically ill patients has not been investigated. This randomized, placebo-controlled, double-blinded Phase II study will test whether intranasal insulin can prevent acute cognitive dysfunction in elderly critically ill patients admitted to the intensive care unit after undergoing cardiac bypass surgery. This study will enroll 60 elderly cardiac surgery patients =65 years old who will receive either 40 IU of aspart insulin or placebo intranasally four times a day for 7 days. Specific Aim 1 will examine the utility of intranasal insulin for reducing POCD in adults =65 years old who are undergoing cardiac surgery, and evaluate its safety in this population. Cognitive testing will occur prior to surgery, 7 days after surgery or at hospital discharge (whichever occurs first) and 6 weeks after hospital discharge. Specific Aim 2 will investigate the utility of intranasal insulin for reducing POD and explore the relationship between POD and subsequent POCD in adults =65 years old undergoing cardiac surgery. This study will achieve several important goals: (1) data from this study will determine whether a multi-center phase III study is warranted and will inform the optimal study design of the phase III trial;(2) this study will yield important prospective longitudinal data on the relationship between POD and POCD in elderly cardiac surgery patients and thus help elucidate the pathogenesis of POCD in an ICU setting: and (3) this study will provide the PI with training and experience in studying neurocognitive outcomes in the elderly critically ill and in the planning and execution of an interdepartmental randomized clinical trial. The skills, data and experience that the PI will gain through this study will directly contribute to her mentored career award application in which she plans to further explore the relationship between POCD and POD in an elderly surgical ICU population and their impact on psychiatric and functional outcomes A multidisciplinary team of experts in critical care trials, delirium, and cognitive decline in elderly patients has been assembled to support and mentor the PI through the successful completion of the study objectives and to help develop her career. PUBLIC HEALTH RELEVANCE: Adults over 65 years old form the fastest growing age group in the U.S. and contribute to over half of all ICU admissions. Delirium and cognitive decline are forms of acute brain dysfunction that 1) commonly occur in elderly cardiac surgery and other patients in the ICU, 2) are associated with poor functional recovery and decreased quality of life, and 3) lack effective preventive or therapeutic treatments. An intervention that reduces acute brain dysfunction can significantly improve the lives of this vulnerable and growing population.